Major depressive disorder (MDD) is a highly prevalent psychiatric condition associated with significant psychosocial sequelae, particularly the early-onset form. Recent advances in the field of epigenetics (i.e., environmentally-induced changes in DNA that affect gene function but not structure) are beginning to shed light on how exposure to stressful life events affords risk on a biologic level for psychiatric phenotypes such as early-onset MDD (EOMDD). Recent data suggests that one possible pathway to mood disorders is via epigenetic alterations to gene expression levels. Given the centrality of adverse life event exposure to depression, epigenetic effects have attracted interest as offering a plausible mechanism by which the environment may alter biological substrates associated with EOMDD and also increase future risk for MDD. We propose to evaluate epigenomic (i.e., genome-wide epigenetic [DNA methylation] and gene expression) mechanisms in a sample of 100 twin pairs, where 50 pairs are discordant for EOMDD, 25 pairs are concordant for EOMDD (positive controls) and 25 pairs are concordant for a negative lifetime history of EOMDD (negative controls), allowing for an unprecedented opportunity to verify epigenetic dysregulation associations that are not confounded by genetic background and/or shared familial factors. A psychiatric history measures lifetime psychiatric conditions, and a comprehensive battery assesses stressful life events, trauma exposures, personality, and stress reactivity (via cortisol) The biological endpoints that will be compared within MZ twin pairs include epigenetic (methylation) and gene expression biomarkers. The power of the discordant MZ twin design stems from its ability to control for the identical genome sequences and familial environmental risk factors shared within twin pairs, leaving only environmental/social experiences (or stochastic molecular events) unique to one member of a twin pair to account for the differential acquisition of epigenomic patterns. The MZ twin pair study design will provide a robust test of: (1) the epigenome's cross-sectional association with EOMDD, (2) the epigenome's ability to predict future depression risk and trajectory, and (3) whether improving depression levels are associated with a reversal of genetic biomarker profiles and vice versa.